The show follows the adventures of S.H.I.E.L.D. - America's top super-spy agency and the country's first and last (non-super powered) line of defense against threats of a global nature. The series follows story concepts introduced in The Avengers such as alien technology left behind by the Chitauri. It also addresses consequences of other elements of the Marvel Cinematic Universe, such as the Super-Soldier Serum that turned scrawny Steve Rogers into the patriotic Captain America back in the 1940s and Gamma radiation, which was responsible for transforming scientist Bruce Banner into a rampaging Hulk.

Agents of S.H.I.E.L.D. stars Clark Gregg reprising the role of Agent Phil Coulson, who appeared in four of the Marvel Cinematic Universe films as well as the Marvel One-Shot shorts. Although his character was seemingly killed off in The Avengers by Loki, Agent Coulson appears to be back in action. The rest of the cast are brand new characters unique not only to the Marvel Movieverse, but also from the comics themselves. Creator Joss Whedon sought to create an original ensemble of character, but place them in a world with a familiar setting. The S.H.I.E.L.D. lineup includes Brett Dalton as neophyte ass-kicker Grant Ward, Chloe Bennet as the rogue computer hacker Skye, Ming-Na Wen as seasoned veteran Melinda May, Iain De Caestecker as computer nerd Leo Fitz and Elizabeth Henstridge as Leo's partner, Jemma Simmons (they are both collectively referred to as Fitzsimmons).

Agents of S.H.I.E.L.D. is the first TV series from Disney's new production company, Marvel Television. Although it is the first show to actually materialize from Marvel Television, the studio has placed several pilot concepts for other Marvel Comics properties into the works.

The entire cast of Agents of S.H.I.E.L.D. appeared at the Marvel panel at the 2013 San Diego Comic-Con.

The music for Agents of S.H.I.E.L.D. was composed by Bear McCreary, who is also known for his haunting scores on such notable programs like the Battlestar Galactica reboot and AMC's The Walking Dead.

Series creator Joss Whedon likes recycling actors from his past projects and Agents of S.H.I.E.L.D. is no exception. In the pilot episode, he brought back Firefly actor Ron Glass to play the role of Doctor Streiten. Also in the pilot, former Angel actor J. August Richards appeared as the featured superhuman in the episode named Mike Peterson.

The pilot episode of the series introduced the S.H.I.E.L.D. flying car, which Agent Coulson has expressed a certain fondness for and has nicknamed "Lola". A precursor to the car was seen in 2011's Captain America: The First Avenger, which was the invention of Howard Stark. The S.H.I.E.L.D. flying car has a long history in related comic book stories and is the second most often-used vehicle in S.H.I.E.L.D.'s arsenal after the Helicarrier.